Activating appendages to induce polypharmacology in peptide hormone analogues, including dual glp-1r / gip agonism

Abstract

Compounds, method of making the compounds, and methods of using the compounds to treat Type 2 diabetes and obesity in mammals, including humans. The compounds are dual GLP-1 receptor and GIP receptor agonists in which at least one side chain of a residue in GLP-1 and/or GIP is modified such that the modified GLP-1 and GIP are agonists of both GLP-1 receptor and GIP receptor.

What is claimed is: 
     
         1 . A method of making dual GLP-1 receptor and GIP receptor agonists, the method comprising modifying at least one side chain of a residue in GLP-1 and/or GIP, to yield a modified GLP-1 and/or GIP, wherein the modified GLP-1 and GIP are agonists of both GLP-1 receptor and GIP receptor. 
     
     
         2 . The method of  claim 1 , wherein the at least one side chain of a residue in GLP-1 and/or GIP is modified to contain a side chain comprising: 
       
         
           
           
               
               
           
         
         wherein: 
         B is an integer of from 1 to 6; 
         T is an integer of from 0 to 6, or the carbon atom bearing the subscript T is a substituted or unsubstituted C 3 -C 6 -cycloalkyl and T=1; and 
         R is selected from the group consisting of polycyclic aromatic hydrocarbons and 
       
       
         
           
           
               
               
           
         
         wherein R 1  is independently selected from the group consisting of an unsubstituted polycyclic aromatic hydrocarbon, a polycyclic aromatic hydrocarbon having up to three substitutions, an unsubstituted heterocycle, a heterocycle having up to three substitutions, a halogen, and 
       
       
         
           
           
               
               
           
         
         wherein R 4 , R 5 , and R 6  are independently selected from the group consisting of H, halogen, —OH, —C 1 -C 6 -linear or branched, unsubstituted or alkyl, and —O—C 1 -C 6 -linear or branched, substituted or unsubstituted alkyl; and 
         R 2  and R 3  are independently selected from the group consisting of H, halogen, —OH, —C 1 -C 6 -linear or branched, substituted or unsubstituted alkyl, —C 1 -C 6 -linear or branched, substituted or unsubstituted alkylaryl, —O—C 1 -C 6 -linear or branched, substituted or unsubstituted alkyl, —O—C 1 -C 6 -linear or branched, substituted or unsubstituted alkylaryl, and the groups listed for R 1 . 
       
     
     
         3 . The method of  claim 1 , consisting essentially of modifying one (1) and only (1) side chain of a residue in the GLP-1 and/or GIP. 
     
     
         4 . The method of  claim 2 , wherein R is 
       
         
           
           
               
               
           
         
       
     
     
         5 . The method of  claim 4 , wherein R 2  R 4 , R 5 , and R 6  are independently selected from the group consisting of a halogen, H, —OH, —CH 3 , and —O—CH 3 . 
     
     
         6 . The method of  claim 5 , wherein “T” and “B” are integers of from 1 to 4, R 1 , R 4 , R 5 , and R 6  are selected from the group consisting of —OH or —O—CH 3 , and R 2  is H or —CH 3 . 
     
     
         7 . The method of  claim 1 , wherein the carbon atom bearing the subscript T is cyclohexyl and T=1. 
     
     
         8 . The method of  claim 1 , wherein at least one other side chain of a residue in GLP-1 and/or GIP is modified to comprise a side chain selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         9 . A compound comprising GLP-1 or GIP in which at least one side chain of a residue in the GLP-1 and/or the GIP is modified to contain a side chain comprising: 
       
         
           
           
               
               
           
         
         wherein: 
         B is an integer of from 1 to 6; 
         T is an integer of from 0 to 6, or the carbon atom bearing the subscript T is a substituted or unsubstituted C 3 -C 6 -cycloalkyl and T=1; and 
         R is selected from the group consisting of polycyclic aromatic hydrocarbons and 
       
       
         
           
           
               
               
           
         
         wherein R 1  is independently selected from the group consisting of an unsubstituted polycyclic aromatic hydrocarbon, halogen, a polycyclic aromatic hydrocarbon having up to three substitutions, an unsubstituted heterocycle, a heterocycle having up to three substitutions, and 
       
       
         
           
           
               
               
           
         
         wherein R 4 , R 5 , and R 6  are independently selected from the group consisting of H, halogen, —OH, —C 1 -C 6 -linear or branched, unsubstituted or alkyl, and —O—C 1 -C 6 -linear or branched, substituted or unsubstituted alkyl; and 
         R 2  and R 3  are independently selected from the group consisting of H, halogen, —OH, —C 1 -C 6 -linear or branched, substituted or unsubstituted alkyl, —C 1 -C 6 -linear or branched, substituted or unsubstituted alkylaryl, —O—C 1 -C 6 -linear or branched, substituted or unsubstituted alkyl, —O—C 1 -C 6 -linear or branched, substituted or unsubstituted alkylaryl, and the groups listed for R 1 ; 
         and salts thereof. 
       
     
     
         10 . The compound of  claim 9 , wherein one (1) and only (1) side chain of a residue in the GLP-1 and/or GIP is modified. 
     
     
         11 . The compound of  claim 9 , wherein R is 
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound of  claim 11 , wherein R 2 , R 4 , R 5 , and R 6  are independently selected from the group consisting of a halogen, H, halogen, —OH, —CH 3 , and —O—CH 3 . 
     
     
         13 . The compound of  claim 12 , wherein “T” and “B” are integers of from 1 to 4, R 4  R 5 , and R 6  are independently selected form the group consisting of —OH and —O—CH 3 , and R 2  is H or —CH 3 . 
     
     
         14 . The compound of  claim 9 , wherein the carbon atom bearing the subscript T is cyclohexyl and T=1. 
     
     
         15 . The compound of  claim 9 , wherein the salt is a pharmaceutically suitable salt. 
     
     
         16 . A compound according to  claim 9 , wherein at least one other side chain of a residue in GLP-1 and/or GIP comprises a side chain selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         17 . A pharmaceutical composition comprising a compound as recited in  claim 9 , optionally in combination with a pharmaceutically suitable carrier. 
     
     
         18 . A method of treating diabetes and/or obesity in a mammal, the method comprising administering an anti-diabetes-effective amount and/or a weight loss-effective amount of a compound as recited in  claim 9  to a mammal. 
     
     
         19 . The method of  claim 18 , comprising administering the compound to a human being.